Container Closure Systems For Biosimilars: Is There Regulatory Difference?

By Fran DeGrazio, Senior Industry & Technical Advisor, Drug Delivery Leader

Biosimilars are one of the industry’s most active growth areas, driven in part by the number of biologic drugs expected to lose patent protection over the next several years. Many of these biosimilars will need to be delivered in conjunction with a delivery device. Therefore, they will be considered as combination products from a regulatory perspective.

Several factors are accelerating interest in this market:

• The biosimilars market is projected by Mordor Intelligence to grow from $41.97 billion in 2025 to $112.93 billion by 2031.
• Recent U.S. FDA policy revisions intended to streamline interchangeability designations may shorten launch timelines, strengthening commercial incentives for biosimilar development.
• Per Modor Intelligence, intravenous administration continues to represent a significant portion of the market, while the subcutaneous segment is expected to grow at a compound annual growth rate above 20%.

Influence Of The GLP-1 Patent Landscape

A key driver in this segment comes from GLP-1 products, which are peptide-based therapies, approaching key patent and exclusivity milestones. Globally, companies in India and China are conducting clinical trials and other technical studies for biosimilar or generic versions of current market-leading products from Novo Nordisk and Eli Lilly.

In the United States, originator patents for leading GLP-1 products generally extend into the 2030s. Even so, some organizations are beginning to position themselves for future competition. For example, Sandoz, a global leader in generic and biosimilar production, announced on June 29, 2026, that it had submitted two abbreviated new drug applications (ANDAs) for generic versions of tirzepatide.

Canada has already reached a key intellectual property milestone for Novo Nordisk’s semaglutide, the active ingredient in the injectable GLP-1 products Wegovy and Ozempic. After a patent maintenance fee was missed, regulatory data exclusivity officially ended on January 4, 2026. This development makes Canada the first major Western market open to generic or biosimilar competition for semaglutide-based GLP-1 products.

Understanding The Various CCS-Related Guidances

In response to industry need, the FDA has recently published a draft guidance entitled,  Biosimilar and Interchangeable Biosimilar Products: Considerations for Container Closure Systems (CCS) and Device Constituent Parts for industry comments. This has been released by CDER (Center for Drug Evaluation and Research) and CBER (Center for Biologics Evaluation and Research). When this document is finalized, it will represent the FDA’s current perspective on this topic.

This guidance is separate and distinct from the one recently published by the FDA as a specific update of the 1999 Container Closure Guidance. That draft guidance is entitled, Container Closure Systems for Human Drugs and Biological Products. You can find my thoughts on it in the Drug Delivery Leader article, “Unpacking The FDA Draft Guidance On Container Closure Systems.”

Another clarification: The guidance on CCS for biosimilars does NOT apply to generic combination products. If an ANDA is being submitted, reference the draft guidance, Comparative Analyses and Related Comparative Use Human Factors Studies for a Drug-Device Combination Product submitted in an ANDA (January 2017).

I offer the reminder that there are two recently published FDA draft guidance documents related to CCS also because there may be some confusion among those in industry working on combination product development about the existence of the dual documents.

What Is Contained In The Biosimilars Container Closure Guidance?

As for the guidance specific to biosimilars, what are the salient points?

Based on my review and experience, the draft guidance does not appear to include anything unusual or unexpected. However, it provides useful clarification for stakeholders who may be less familiar with FDA expectations for biosimilar and interchangeable biosimilar applications submitted under section 351(k) of the Public Health Service Act.

The guidance helps clarify the types of data and information needed to support a demonstration of biosimilarity or interchangeability, particularly as they relate to:

• container closure systems
• device constituent parts
• the relationship between the biologic product, its primary packaging, and any associated delivery device

Overall, the document reinforces FDA’s expectations that these elements should be evaluated as part of the overall product presentation and supported with appropriate data in the application.

5 Key Takeaways From The Biosimilars Guidance

Presented below are some of the key highlights and takeaways from the draft guidance, along with my thoughts and recommendations regarding the implications of each:

#1: Quality Counts Just The Same

From the guidance:

“Expectations regarding product quality for the CCS and the device constituent parts are the same as for proposed biological products.”

My take on implications:

Although a proposed product may be submitted as a biosimilar, FDA expects the quality of the drug product and any combination-product elements to be comparable to the reference product. Sponsors should therefore ensure that the container closure system, device constituent parts, and overall product presentation meet the same quality expectations as the originator product. This means that a risk-based approach to testing and product/process understanding is still needed for biosimilars.

#2: There’s No Turning Away From Testing

From the guidance:

 “The BLA should include data from appropriate studies that demonstrate compatibility between the device constituent part and the final formulation of the biological constituent part.”

My take on implications:

Extractable/leachables testing, performance testing, and other work such as stabilities studies need to be completed and submitted for regulatory review.

It is important to understand that execution of development and commercialization of a biosimilar is no different than that of an originator’s product from a quality or compliance perspective. There are no shortcuts when it comes to quality and compliance!

#3: Differences Must Be Documented And, If Necessary, Defended

From the guidance:

“Sponsors should use comparative analyses to identify all differences between the user interface of the proposed biosimilar or interchangeable biosimilar combination product and the user interface of the reference product.”

My take on implications:

 FDA recommends physical comparison, comparative task analyses, and a line-by-line review of the label vs that for the reference product. Any differences must be noted, and they must be assessed for risk. What’s identified and assessed must be documented, along with any conclusions, so that the regulators can understand why decisions were made. For instance, if there is a difference of a line within the IFU why is it necessary to be different?

#4: Even Minor Differences May Require Additional Data

From the guidance:

“A  stepwise, systematic approach for  sponsors to use in identifying and analyzing differences in the user interface between a proposed biosimilar and the user interface of its reference product “ is suggested.

My take on implications:

All differences relating to user interface should be identified, then combination product Critical Tasks must be identified. If design differences are present, the sponsor should evaluate the risk associated with each difference and determine whether it could affect a critical task. For each difference identified, the associated risk must be clarified. A use-related risk analysis (URRA) is helpful to perform and document this activity.

Any differences should be classified as minor or ‘other’ design difference. An example of a difference could be the addition of audible feedback for an autoinjector when the originator’s product did not include this feature. Although it may have been added to address a potential weakness in the originator’s delivery system, that feature would still be considered a difference. For that reason, its Human Factors implications must be understood and addressed.

If there are no design differences between the user interfaces, FDA will likely not require additional data to support approval.

Because FDA may not view every user-interface difference as minor, sponsors should engage with the agency early to confirm what additional information may be needed. Depending on the nature and risk of the difference, a Human Factors Validation Study may be required. An example here could be a different color label or button on a device, which may be seen as a minor difference by the engineers performing the evaluation. Due to the FDA having history across a broad range of products and user groups, its perspective may be different. It is always best to engage early to avoid downstream delays.

#5: A Change In Presentation Will Be Deemed ‘Different’

From the guidance:

“If an applicant intends to develop and seek licensure of a proposed combination product in a different presentation than its reference product, it is likely there will be differences.”

My take on implications:

When an applicant proposes a presentation that is not marketed for the reference product, FDA is likely to view the change as creating a user-interface difference. Even with a different presentation, the proposed product must continue to meet the applicable standards for biosimilarity.

The draft guidance describes an example scenario in which the reference product is supplied in a stopper/vial system, while the proposed biosimilar is introduced in a prefilled syringe (PFS). In this situation, the PFS presentation should maintain the same dosage form, strength, and route of administration as the reference product.

Within the draft guidance, there is major focus on Human Factors understanding and comparability between the biosimilar presentation and the reference product. Because a change in presentation may affect how users interact with the product, applicants should expect to provide additional Human Factors information to support the proposed presentation.

CCS Thinking Within Product Lifecycle Planning

In previous articles (e.g., “7 Management Strategies For Combination Product Regulatory Success”), I have urged attention to lifecycle management early in defining a product for development. Of course, unanticipated needs for shifts in direction may occur; nevertheless, there should be a strategic plan established and understood within the development team in terms of the long-range goals of the program.

For biosimilar product development, the draft guidance on CCS  should be well understood within the context of long-range planning. Ultimately, it is important that sponsors consider long-term presentation management strategies when establishing the Target Product Profile (TPP).

For instance, many drugs may be launched in a vial/stopper system. However, there may be a goal to eventually deliver as a prefilled syringe system. If this is the case, that goal should be defined early in the TPP for the development program. If an initial presentation is in a prefillable syringe system and the ultimate goal is to be in an autoinjector, understanding this early can be helpful in choosing suppliers, defining critical aspects of components and constituent parts, and addressing other factors in working to avoid unexpected problems in lifecycle management.

Considerations that the program’s goals and related TPP should reflect include intended population, clinical efficacy, dosing and administration, and other technical and business objectives. Weaving those aspects into the goals and TPP is in line with the concept of “beginning with the end in mind,” a concept quite common to Quality by Design or Design & Development Controls in both the pharmaceutical and medical device industry.

As my reflections on the draft guidance illustrate, thinking through product and presentation strategies early is sound practice that applies not only to biologic drugs but to biosimilars as well. One thing is always true about biopharma product development: Ensuring that everyone is working towards the same goal is critical for long-term success.